Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Heparan Sulfate Facilitates Binding of hIFNγ to its Cell-Surface Receptor hIFNGR1

Version 1 : Received: 1 July 2022 / Approved: 5 July 2022 / Online: 5 July 2022 (04:43:05 CEST)

A peer-reviewed article of this Preprint also exists.

Miladinova, E.; Lilkova, E.; Krachmarova, E.; Malinova, K.; Petkov, P.; Ilieva, N.; Nacheva, G.; Litov, L. Heparan Sulfate Facilitates Binding of hIFNγ to Its Cell-Surface Receptor hIFNGR1. Int. J. Mol. Sci. 2022, 23, 9415. Miladinova, E.; Lilkova, E.; Krachmarova, E.; Malinova, K.; Petkov, P.; Ilieva, N.; Nacheva, G.; Litov, L. Heparan Sulfate Facilitates Binding of hIFNγ to Its Cell-Surface Receptor hIFNGR1. Int. J. Mol. Sci. 2022, 23, 9415.

Abstract

The extremely controversial conclusions about the function of human interferon-gamma (hIFNγ) C-terminus as well as the lack of a consistent model explaining its role in the receptor binding prompted us to scrutinize the interaction of hIFNγ with its extracellular receptor hIFNGR1 in different scenarios by means of molecular dynamics simulations. We find that the two molecules alone fail to form a stable complex but the presence of heparan-sulfate-like oligosaccharides largely facilitates the process by both demobilizing the highly flexible C-termini of the cytokine and assisting in the proper positioning of its globule between the receptor subunits. An antiproliferative-activity essay on cells depleted from surface sulfation confirms qualitatively the simulation-based multistage complex-formation model. Our results reveal the key role of HS and its proteoglycans in all processes involving hIFNγ signalling.

Keywords

human interferon gamma; human interferon gamma receptor; receptor binding; heparan sulfate; co-receptor; molecular dynamics simulations; sodium chlorate; kynurenine antiproliferative assays; hIFNγ signalling

Subject

Biology and Life Sciences, Biophysics

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